A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN

J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):851-8. doi: 10.1136/jnnp-2015-311541. Epub 2016 Jan 8.

Abstract

Objective: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns.

Methods: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs.

Results: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002).

Conclusions: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amyotrophic Lateral Sclerosis / diagnosis*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Connectin / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Prognosis

Substances

  • Connectin
  • TTN protein, human